Serpinb9, also known as Proteinase Inhibitor 9 (PI-9), is a well-known endogenous inhibitor of Granzyme B (GzmB) [3]. GzmB is a cytotoxic molecule secreted by cytotoxic T lymphocytes and natural killer cells, and Serpinb9 acts as a protective mechanism against the potentially harmful effects of GzmB within immune system cells. It is involved in pathways related to immune responses, cell death regulation, and prevention of immunopathology [3]. Genetic models, especially KO mouse models, are valuable for studying its functions.

Genetic ablation of Serpinb9 in mice leads to the death of tumor cells in a granzyme B-dependent manner, and Sb9-deficient mice exhibit protective T cell-based host immunity to tumors, with a decline in GrB-expressing immunosuppressive cells in the tumor microenvironment (TME) [1]. In vivo CRISPR screens in mouse lung cancer models also recovered Serpinb9 as an immune evasion factor [2]. In addition, overexpression of Serpinb9 in non-seminomatous germ cell tumors is associated with immune escape, as it is inversely correlated with the number of tumor-infiltrating CD8-positive cells [4].

In conclusion, Serpinb9 plays a crucial role in regulating immune responses and cell death. Gene-knockout mouse models have revealed its significance in tumor-immune interactions, especially in cancer immunotherapy resistance. Understanding Serpinb9's functions can potentially lead to new therapeutic strategies for cancers and other immune-related diseases.

References:

1. Jiang, Liwei, Wang, Yi-Jun, Zhao, Jing, Dhe-Paganon, Sirano, Abdi, Reza. . Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy. In Cell, 183, 1219-1233.e18. doi:10.1016/j.cell.2020.10.045. https://pubmed.ncbi.nlm.nih.gov/33242418/

2. Dervovic, Dzana, Malik, Ahmad A, Chen, Edward L Y, Jackson, Hartland W, Schramek, Daniel. 2023. In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer. In Nature communications, 14, 3150. doi:10.1038/s41467-023-38841-7. https://pubmed.ncbi.nlm.nih.gov/37258521/

3. Huang, Haozhe, Mu, Yiqing, Li, Song. 2024. The biological function of Serpinb9 and Serpinb9-based therapy. In Frontiers in immunology, 15, 1422113. doi:10.3389/fimmu.2024.1422113. https://pubmed.ncbi.nlm.nih.gov/38966643/

4. Anami, Toshiki, Ibe, Yuki, Li, Lianbo, Hibi, Taizo, Kamba, Tomomi. 2023. Overexpression of SerpinB9 in non-seminomatous germ cell tumors. In Medical molecular morphology, 57, 68-75. doi:10.1007/s00795-023-00374-9. https://pubmed.ncbi.nlm.nih.gov/37991604/